It is known that 2-fluoroacrylic esters are important as intermediates for pharmaceutical and agricultural chemicals and as monomers for functional polymers. Patent Publication 1 discloses, as a conventional production technique relevant to the present invention, a process of producing 2-bromo-2-fluoropropionic ester by reaction of 2-fluoropropionic ester with carbon tetrabromide or bromine in the presence of a base. Further, Patent Document 2 discloses a process for producing 2-fluoroacrylic ester by dehydrobromination reaction of 2-bromo-2-fluoropropionic ester in the presence of a basic compound.
Prior Art Documents
Patent Documents
Patent Document 1: Japanese Laid-Open Patent Publication No. 2001-139519
Patent Document 2: Japanese Laid-Open Patent Publication No. 2001-172223
Problems to be Solved by the Invention
In the production process of Patent Document 1, it is necessary to conduct the reaction under very-low-temperature conditions (i.e. at a temperature not exceeding −70° C.) as there occurs an unstable anion by the reaction of the 2-fluoropropionate with the base. It is also necessary to use a stoichiometric amount of expensive organic lithium compound (such as lithium dialkylamide or n-butyl lithium) as the base.
In the production process of Patent Document 2, it is necessary to use a nitrogen-containing basic compound against the ester and, particularly in the case of expecting high yield, use a stoichiometric amount of expensive 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Accordingly, there has been a strong demand for an industrial production process of 2-fluoroacrylic esters that does not need very-low-temperature equipment and expensive reagent.
It is therefore an object of the present invention to solve the above prior art problems and provide an industrial production process of 2-fluoroacrylic esters that does not need very-low-temperature equipment and expensive reagent.
Means for Solving the Problems
The present inventors have made extensive researches in view of the above prior art problems and, as a result, have found that it is possible to produce a 2-fluoroacrylic ester by reacting a 2-fluoropropionic ester with a nitrogen-bromine bond-containing brominating agent in the presence of a radical initiator (bromination reaction), and then, reacting the 2-bromo-2-fluoropropionic ester with a base (dehydrobromination reaction).
It is preferable that, in the ester moiety of the 2-fluoropropionic ester, R is either a methyl group, an ethyl group, a 2,2,2-trifluoroethyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group. The 2-fluoropropionic ester in which R is methyl, ethyl, 2,2,2-trifluoroethyl or 1,1,1,3,3,3-hexafluoroisopropyl can be easily obtained on a large scale. Further, the 2-fluoroacrylic ester produced from such a 2-fluoropropionic ester is particularly important and preferred in terms of usability.
As the nitrogen-bromine bond-containing brominating agent, N-bromosuccinimide (NBS) is preferred. This brominating agent can be easily obtained on a large scale and at low cost and exhibits good reactivity. As the radical initiator for the bromination reaction, 2,2′-azobisisobutyronitrile (AIBN), 1,1′-azobis(cyclohexane-1-carbonitrile) (V-40) and benzoyl peroxide (BPO) are preferred. These radical initiators can be easily obtained on a large scale and at low cost and each exhibit good reactivity.
It is further preferable to use, as the base in the dehydrobromination reaction, a stoichiometric amount of alkali metal carbonate or tri-n-butylamine in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). This base allows the reaction to proceed at low cost even on a large scale while maintaining good reactivity.
In order to prevent self-polymerization of the 2-fluoroacrylic ester, the dehydrobromination reaction and the distillation purification may be performed in the presence of a polymerization inhibitor. As the polymerization inhibitor, phenothiazine, hydroquinone and 2,6-di-tert-butyl-4-methylphenol (BHT) are preferred. These polymerization inhibitors can be easily obtained on a large scale and at low cost and each show good self-polymerization prevention effects. Furthermore, the distillation purification may be performed by entraining air or oxygen in the 2-fluoroacrylic ester (this distillation operation is hereinafter called “aeration distillation”) in order to prevent self-polymerization of the 2-fluoroacrylic ester. It is preferable in the aeration distillation to entrain air in the 2-fluoroacrylic ester so that the distillation can be performed safely with less equipment load for equivalent self-polymerization prevention effects.
As mentioned above, there have been found the useful techniques for production of the 2-fluoroacrylic ester. The present invention is based on these findings.
Namely, the present invention includes the following features.
[Inventive Feature 1]
A process of producing a 2-fluoroacrylic ester of the general formula [3], comprising:
a bromination step of converting a 2-fluoropropionic ester of the general formula [1] to a 2-bromo-2-fluoropropionic ester of the general formula [2] by reaction of the 2-fluoropropionic ester with a nitrogen-bromine bond-containing brominating agent in the presence of a radical initiator; and
a dehydrobromination step of reacting the 2-bromo-2-fluoropropionic ester with a base
where Me represents a methyl group; and R represents an alkyl group or a fluorine-substituted alkyl group.
[Inventive Feature 2]
The process of producing the 2-fluoroacrylic ester according to Inventive Feature 1, wherein, in an ester moiety of the ester, R is either a methyl group, an ethyl group, a 2,2,2-trifluoroethyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group.
[Inventive Feature 3]
The process of producing the 2-fluoroacrylic ester according to Inventive Feature 1 or 2, wherein the nitrogen-bromine bond-containing brominating agent used in the bromination step is N-bromosuccinimide (NBS).
[Inventive Feature 4]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 3, wherein the radical initiator used in the bromination step is either 2,2′-azobisisobutyronitrile (AIBN), 1,1′-azobis(cyclohexane-1-carbonitrile) (V-40) or benzoyl peroxide (BPO).
[Inventive Feature 5]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 4, wherein an alkali metal carbonate is used stoichiometrically in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in the dehydrobromination step.
[Inventive Feature 6]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 4, wherein tri-n-butylamine is used stoichiometrically in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in the dehydrobromination step.
[Inventive Feature 7]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 6, wherein the dehydrobromination step is performed in the presence of a polymerization inhibitor.
[Inventive Feature 8]
The process of producing the 2-fluoroacrylic ester according to Inventive Feature 7, wherein the polymerization inhibitor is either phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT).
[Inventive Feature 9]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 8, further comprising subjecting the 2-fluoroacrylic ester to distillation purification in the presence of a polymerization inhibitor.
[Inventive Feature 10]
The process of producing the 2-fluoroacrylic ester according to Inventive Feature 9, wherein the polymerization inhibitor is either phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT).
[Inventive Feature 11]
The process of producing the 2-fluoroacrylic ester according to any one of Inventive Features 1 to 10, further comprising subjecting the 2-fluoroacrylic ester to distillation purification while entraining air or oxygen in the 2-fluoroacrylic ester.
In the production process of the present invention, there are no need to adopt very-low-temperature conditions and no need to use a stoichiometric amount of expensive reagent. It is therefore possible that the target 2-fluoroacrylic ester can be produced at low cost. As moderate production conditions are adopted in the present invention, almost no hydrolysis of the ester moiety occurs throughout the bromination and dehydrobromination steps. This eliminates the need for complicated operation of converting the corresponding carboxylic acid to the target ester compound. Further, the production process of the present invention is suitable in terms of toxic waste reduction as the 2-fluoropropionic ester can be used in an excessive amount so as to serve not only as the raw substrate material but also as a reaction solvent in the bromination step and thereby avoid the use of a chlorinated reaction solvent such as carbon tetrachloride frequently used for halogenation.